The exact means by which kidneys extract and utilize more glutamine during metabolic acidosis is uncertain. This aspect of metabolism is important, for urinary ammonia produced from the nitrogens of glutamine plays a major role in systemic acid-base balance and the decarboxylation of the carbon skelton of glutamine provides fuel for many metabolic processes. It is accepted generally that ammonia is produced from glutamine by two pathways, via phosphate dependent glutaminase (PDG) and glutamate dehydrogenase (GD). The GD pathway may be key to the adaptation in ammonia production during acidosis, because glutamate is known to inhibit the PDG pathways. Faster removal of glutamate via the GD route would increase ammoniagenesis on its own and by lowering intramitochondrial glutamate levels, deinhibit the PDG pathway, and increase ammoniagenesis through the PDG pathway. We wish a) to prove that enhancement in the GD reaction does play an important role in regulating renal ammoniagenesis during acidosis, b) to determine what mechanisms enhance the GD pathway during acidosis, and c) to study other potential mechanisms affecting glutamine metabolism during acidosis. In this proposal, we have outlined in vivo studies with dogs and in vitro studies with rats and dogs to accomplish these goals. While we are primarily interested in understanding renal glutamine metabolism and its response to acidosis, this has led us and undoubtedly will lead us to observations which contribute toward understanding the metabolism of and interaction between the other major renal fuels (lactate, fatty acids, citrate and glucose). In addition the metabolism of renal cells undergoing ATN, during regeneration from injury, and in the hypertensive states may differ in their utilization of fuels and will be investigated.